Devices and methods for vestibular and/or cranial nerve stimulation

ABSTRACT

An in-ear stimulator for administering thermal stimulation to the ear canal of a subject includes (a) an earpiece configured to be insertable into the ear canal of said subject, the earpiece having an outer surface and an internal cavity formed therein, the internal cavity having an inner surface; and (b) at least one thermoelectric device thermally coupled to the earpiece internal cavity inner surface.

RELATED APPLICATIONS

This application claims priority to (a) U.S. Provisional Application No.61/287,873 (attorney docket number 9767-3PR), filed Dec. 18, 2009; (b)U.S. Provisional Application No. 61/303,984 (attorney docket number9767-3PR2), filed Feb. 12, 2010; and (c) U.S. Provisional Patent No.61/304,059 (attorney docket number 9767-32PR), filed Feb. 12, 2010 andis related to (a) U.S. patent application Ser. No. 12/669,684 (attorneydocket number 9767-2), U.S. patent application Ser. No. 12/699,374(attorney docket number 9767-2IP), U.S. patent application Ser. No.12/704,872 (attorney docket number 9767-2IP2), U.S. patent applicationSer. No. 11/972,267 (attorney docket number 9767-31), U.S. patentapplication Ser. No. 12/166,953 (attorney docket number 9767-31IP) andU.S. patent application Ser. No. 12/693,016 (attorney docket number9767-31IP2); (b) U.S. Provisional Application Nos. 60/884,546,60/908,261, 60/953,700 and 61/224,668 (attorney docket number9767-13PR); (c) PCT Application No. PCT/US2008/071935 (attorney docketnumber 9767-2WO), and (d) U.S. application Ser. No. 12/970,347 (attorneydocket number 9767-32, filed Dec. 16, 2010), the disclosure of each ofwhich is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to apparatuses and associated methodsuseful for delivering stimulation to the nervous system and/or thevestibular system of an individual, thereby inducing physiologicalchanges in the individual and/or treating a disorder or symptom of theindividual.

BACKGROUND

Caloric vestibular stimulation (“CVS”) has long been known as adiagnostic procedure for testing the function of the vestibular system.In the traditional hospital setting, water caloric tests are used toassess levels of consciousness during acute or chronic brain injury. Thebrain injury may be due to head trauma or a central nervous system eventsuch as a stroke. Other brain injuries occur in the presence ofmetabolic abnormalities (e.g., kidney disease, diabetes), seizures, ortoxic levels of controlled substances or alcohol.

U.S. Patent Publication No. 2003/0195588 to Fischell et al. discusses astimulator in an ear canal that is adapted to provide magnetic,electrical, audible, tactile or caloric stimulation. Fischell proposes aring-shaped caloric transducer strip on an ear canal sensor/stimulatorsystem that may result in relatively slow thermal changes of the earcanal.

Accordingly, apparatuses and associated methods useful for deliveringstimulation to the nervous system and/or the vestibular system of anindividual that may be capable of relatively fast temperature changesare potentially beneficial to take full advantage of physiologicalresponses that are useful in diagnosing and/or treating a variety ofmedical conditions.

SUMMARY OF EMBODIMENTS OF THE INVENTION

According to some embodiments, an in-ear stimulator for administeringthermal stimulation to the ear canal of a subject includes (a) anearpiece configured to be at least partially insertable into the earcanal of the subject; and (b) at least one thermoelectric devicethermally coupled to the earpiece and configured to heat and/or cool theearpiece to thereby heat and/or cool the ear canal of the subject.

In some embodiments, the stimulator further comprises a heat sinkthermally coupled to the at least one thermoelectric device andconfigured for positioned outside the ear canal of a subject. The heatsink may include a generally planar surface, and the earpiece may have acorresponding cooperating planar surface. The at least onethermoelectric device is mounted between the heat sink planar surfaceand the cooperating portion of the earpiece planar surface. The heatsink outer portion may include a plurality of fins. The heat sink mayinclude aluminum. The heat sink may have a weight between about 50 gramsand about 55 grams.

In some embodiments, the earpiece is formed from a rigid,thermally-conductive material. The earpiece may include aluminum. Theearpiece may weigh about 12 grams or less.

In some embodiments, the at least one thermoelectric device includes aplurality of thermoelectric devices. The plurality of thermoelectricdevices may be thermally coupled to one another. The at least onethermoelectric device may include a thin film thermoelectric device.

In some embodiments, the earpiece is thermally coupled to a first sideof the at least one thermoelectric device and the heat sink is thermallycoupled to an opposing second side of the at least one thermoelectricdevice.

In some embodiments, the earpiece is conical in shape. The earpiece mayinclude a circular cone. The earpiece may include a conical apex of theconical shape that has been blunted to form a dome-shaped point. Theearpiece may include a generally cylindrical base having opposite firstand second ends, and the base defines a longitudinal centerline. Anextended portion extends from the second end of the cylindrical base,and the dome-shaped point is offset from the longitudinal centerline.The cross-sectional area of the extended portion decreases as a functionof distance away from the base. The extended portion may taper unevenlyfrom the cylindrical base to the dome-shaped point.

In some embodiments, the stimulator includes a head piece, and the headpiece is configured for positioning the earpiece in the ear canal of thesubject.

In some embodiments, an in-ear stimulator for administering thermalstimulation to the ear canals of a subject includes (a) a first earpiececonfigured to be at least partially insertable into the right ear canalof the subject; (b) a second earpiece configured to be at leastpartially insertable into the left ear canal of the subject; (c) atleast one thermoelectric device thermally coupled to the first earpieceand configured to heat and/or cool the first earpiece to therebythermally stimulate the right ear canal of the subject; (d) at least onethermoelectric device thermally coupled to the second earpiece andconfigured to heat and/or cool the second earpiece to thereby thermallystimulate the left ear canal of the subject; (e) a headpiece configuredto position the first earpiece in the right ear canal of the subject andto position the second earpiece in the left ear canal of the subject.

In some embodiments, the headpiece comprises a flexible or adjustable,band.

In some embodiments, a first heat sink is thermally coupled to the atleast one thermoelectric device coupled to the first earpiece; and asecond heat sink is thermally coupled to the at least one thermoelectricdevice coupled to the first earpiece.

In some embodiments, methods for delivering caloric stimulation to asubject include positioning at least a portion of an in-ear stimulatorin an ear canal of the subject. The in-ear stimulator includes (a) anearpiece configured to be at least partially insertable into the earcanal of the subject; and (b) at least one thermoelectric devicethermally coupled to the earpiece and configured to heat and/or cool theearpiece to thereby thermally stimulate the ear canal of the subject. Atime-varying thermal waveform is delivered to the at least onethermoelectric device such that the thermoelectric device effectscorresponding temperature changes to the earpiece to deliver caloricstimulation to the subject.

In some embodiments, the stimulator further comprises a heat sinkpositioned in the earpiece internal cavity, and the heat sink isthermally coupled to the at least one thermoelectric device.

In some embodiments, an in-ear stimulator for administering thermalstimulation to the ear canal of a subject includes a heat sink thermallycoupled to at least one thermoelectric device and having at least anouter portion of the heat sink that is configured for positioningoutside the ear canal of a subject. The at least one thermoelectricdevice is configured to thermally stimulate the ear canal of thesubject.

In some embodiments, the heat sink further includes an inner portionthat is configured for positioning inside the ear canal of the subject.The at least one thermoelectric device is mounted on the inner portionof the heat sink. The heat sink outer portion may include a plurality offins. The heat sink may include aluminum. The heat sink may have aweight between about 50 grams and about 55 grams. In some embodiments,the stimulator includes a sleeve that extends over the heat skink innerportion and the at least one thermoelectric device.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of the specification, illustrate embodiments of the invention and,together with the description, serve to explain principles of theinvention.

FIG. 1 is a front view of an in-ear stimulation apparatus according tosome embodiments of the present invention.

FIG. 2 is an exploded perspective view of one side of the in-earstimulation apparatus of FIG. 1.

FIG. 3 is a perspective view of the right side of an earpiece andearphones of the in-ear stimulation apparatus of FIG. 1.

FIG. 4 is a cut-away cross-sectional view of the earpiece of the in-earstimulation apparatus of FIG. 1 inserted into the ear canal of asubject.

FIG. 5A is a perspective view of the earpiece of the in-ear stimulationapparatus of FIG. 1.

FIG. 5B is a side view of the earpiece of the in-ear stimulationapparatus of FIG. 1.

FIG. 5C is a side cross-sectional view of the earpiece of the in-earstimulation apparatus of FIG. 1.

FIG. 5D is a top view of the earpiece of the in-ear stimulationapparatus of FIG. 1.

FIG. 6A is a side perspective view of an earpiece for in-ear stimulationaccording to some embodiments of the present invention.

FIG. 6B is a side view of the earpiece of FIG. 6A.

FIG. 6C is a side cross-sectional view of the earpiece of FIG. 6A.

FIG. 6D is a top view of the earpiece of FIG. 6A.

FIG. 7A is a side perspective view of an earpiece for in-ear stimulationaccording to some embodiments of the present invention.

FIG. 7B is a side view of the earpiece of FIG. 7A.

FIG. 7C is a side cross-sectional view of the earpiece of FIG. 7A.

FIG. 7D is a top view of the earpiece of FIG. 7A.

FIG. 8A is a side perspective view of an earpiece for in-ear stimulationaccording to some embodiments of the present invention.

FIG. 8B is a side view of the earpiece of FIG. 8A.

FIG. 8C is a side cross-sectional view of the earpiece of FIG. 8A.

FIG. 8D is a top view of the earpiece of FIG. 8A.

FIG. 9 is an exploded perspective view of the earpiece connecting to thethermoelectric devices (TEDs) and the heat sink of the in-ear stimulatorof FIG. 1.

FIG. 10 is an assembled, side view of the earpiece connecting to theTEDs and the heat sink of the in-ear stimulator of FIG. 9.

FIG. 11A is a perspective back view of the heat sink of the in-earstimulation apparatus of FIG. 1.

FIG. 11B is a side view of the heat sink of FIG. 11B.

FIG. 12 is a schematic diagram of a heat sink and thermoelectric deviceaccording to some embodiments of the present invention.

FIG. 13 is a block diagram of an exemplary controller for controlling athermal variation or waveform to a TED apparatus according toembodiments of the present invention.

FIGS. 14A-14F are exemplary thermal waveforms that may be administeredto the ear canal using a TED apparatus according to some embodiments ofthe present invention.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

The present invention now will be described hereinafter with referenceto the accompanying drawings and examples, in which embodiments of theinvention are shown. This invention may, however, be embodied in manydifferent forms and should not be construed as limited to theembodiments set forth herein. Rather, these embodiments are provided sothat this disclosure will be thorough and complete, and will fullyconvey the scope of the invention to those skilled in the art.

Like numbers refer to like elements throughout. In the figures, thethickness of certain lines, layers, components, elements or features maybe exaggerated for clarity.

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention. Asused herein, the singular forms “a,” “an” and “the” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise. It will be further understood that the terms “comprises”and/or “comprising,” when used in this specification, specify thepresence of stated features, steps, operations, elements, and/orcomponents, but do not preclude the presence or addition of one or moreother features, steps, operations, elements, components, and/or groupsthereof. As used herein, the term “and/or” includes any and allcombinations of one or more of the associated listed items. As usedherein, phrases such as “between X and Y” and “between about X and Y”should be interpreted to include X and Y. As used herein, phrases suchas “between about X and Y” mean “between about X and about Y.” As usedherein, phrases such as “from about X to Y” mean “from about X to aboutY.”

Unless otherwise defined, all terms (including technical and scientificterms) used herein have the same meaning as commonly understood by oneof ordinary skill in the art to which this invention belongs. It will befurther understood that terms, such as those defined in commonly useddictionaries, should be interpreted as having a meaning that isconsistent with their meaning in the context of the specification andrelevant art and should not be interpreted in an idealized or overlyformal sense unless expressly so defined herein. Well-known functions orconstructions may not be described in detail for brevity and/or clarity.

It will be understood that when an element is referred to as being “on,”“attached” to, “connected” to, “coupled” with, “contacting,” etc.,another element, it can be directly on, attached to, connected to,coupled with or contacting the other element or intervening elements mayalso be present. In contrast, when an element is referred to as being,for example, “directly on,” “directly attached” to, “directly connected”to, “directly coupled” with or “directly contacting” another element,there are no intervening elements present. It will also be appreciatedby those of skill in the art that references to a structure or featurethat is disposed “adjacent” another feature may have portions thatoverlap or underlie the adjacent feature.

Spatially relative terms, such as “under,” “below,” “lower,” “over,”“upper” and the like, may be used herein for ease of description todescribe one element or feature's relationship to another element(s) orfeature(s) as illustrated in the figures. It will be understood that thespatially relative terms are intended to encompass differentorientations of the device in use or operation in addition to theorientation depicted in the figures. For example, if the device in thefigures is inverted, elements described as “under” or “beneath” otherelements or features would then be oriented “over” the other elements orfeatures. Thus, the exemplary term “under” can encompass both anorientation of “over” and “under.” The device may be otherwise oriented(rotated 90 degrees or at other orientations) and the spatially relativedescriptors used herein interpreted accordingly. Similarly, the terms“upwardly,” “downwardly,” “vertical,” “horizontal” and the like are usedherein for the purpose of explanation only unless specifically indicatedotherwise.

It will be understood that, although the terms “first,” “second,” etc.may be used herein to describe various elements, these elements shouldnot be limited by these terms. These terms are only used to distinguishone element from another. Thus, a “first” element discussed below couldalso be termed a “second” element without departing from the teachingsof the present invention. The sequence of operations (or steps) is notlimited to the order presented in the claims or figures unlessspecifically indicated otherwise.

As used herein, the term “vestibular system” has the meaning ascribed toit in the medical arts and includes but is not limited to those portionsof the inner ear known as the vestibular apparatus and thevestibulocochlear nerve. The vestibular system, therefore, furtherincludes, but is not limited to, those parts of the brain that processsignals from the vestibulocochlear nerve.

“Treatment,” “treat” and “treating” refer to reversing, alleviating,reducing the severity of, delaying the onset of, inhibiting the progressof, or preventing a disease or disorder as described herein, or at leastone symptom of a disease or disorder as described herein (e.g., treatingone or more of tremors, bradykinesia, rigidity or postural instabilityassociated with Parkinson's disease; treating one or more of intrusivesymptoms (e.g., dissociative states, flashbacks, intrusive emotions,intrusive memories, nightmares, and night terrors), avoidant symptoms(e.g., avoiding emotions, avoiding relationships, avoidingresponsibility for others, avoiding situations reminiscent of thetraumatic event), hyperarousal symptoms (e.g., exaggerated startlereaction, explosive outbursts, extreme vigilance, irritability, panicsymptoms, sleep disturbance) associated with post-traumatic stressdisorder). In some embodiments, treatment may be administered after oneor more symptoms have developed. In other embodiments, treatment may beadministered in the absence of symptoms. For example, treatment may beadministered to a susceptible individual prior to the onset of symptoms(e.g., in light of a history of symptoms and/or in light of genetic orother susceptibility factors). Treatment may also be continued aftersymptoms have resolved—for example, to prevent or delay theirrecurrence. Treatment may comprise providing neuroprotection, enhancingcognition and/or increasing cognitive reserve. Treatment may be as anadjuvant treatment as further described herein.

“Adjuvant treatment” as described herein refers to a treatment sessionin which the patient benefit is reducing or eliminating the need foranother medication or treatment, such as a drug treatment or electricalstimulus.

“Chronic treatment,” “Chronically treating,” or the like refers to atherapeutic treatment carried out at least 2 to 3 times a week (or insome embodiments at least daily) over an extended period of time(typically at least one to two weeks, and in some embodiments at leastone to two months), for as long as required to achieve and/or maintaintherapeutic efficacy for the particular condition or disorder for whichthe treatment is carried out.

“Waveform” or “waveform stimulus” as used herein refers to the thermalstimulus (heating, cooling) delivered to the ear canal of a subjectthrough a suitable apparatus to carry out the methods described herein.“Waveform” is not to be confused with “frequency,” the latter termconcerning the rate of delivery of a particular waveform. The term“waveform” is used herein to refer to one complete cycle thereof, unlessadditional cycles (of the same, or different, waveform) are indicated.As discussed further below, time-varying waveforms are preferred oversquare waveforms in carrying out the present invention.

In general, a waveform stimulus used to carry out the present inventioncomprises a leading edge, a peak, and a trailing edge. If a firstwaveform stimulus is followed by a second waveform stimulus, then theminimal stimulus point therebetween is referred to as a trough.

The first waveform of a treatment session is initiated at a start point,which start point may be the at or about the subject's body temperatureat the time the treatment session is initiated (typically a range ofabout 34 to 38 degrees Centigrade, around a normal body temperature ofabout 37 degrees Centigrade. The lower point, 34, is due to the coolnessof the ear canal. It typically will not be above about 37 unless thepatient is febrile). Note that, while the subject's ear canal may beslightly less than body temperature (e.g., about 34 to 36 degreesCentigrade), the starting temperature for the waveform is typically bodytemperature (the temp of the inner ear), or about 37 degrees Centigrade.In some embodiments, however, the temperature of the treatment devicemay not have equilibrated with the ear canal prior to the start of thetreatment session, and in such case the start point for at least thefirst waveform stimulus may be at a value closer to room temperature(about 23 to 26 degrees Centigrade).

The waveform leading edge is preferably ramped or time-varying: that is,the amplitude of the waveform increases through a plurality of differenttemperature points over time (e.g., at least 5, 10, or 15 or moredistinct temperature points, and in some embodiments at least 50, 100,or 150 or more distinct temperature points, from start to peak). Theshape of the leading edge may be a linear ramp, a curved ramp (e.g.,convex or concave; logarithmic or exponential), or a combinationthereof. A vertical cut may be included in the waveform leading edge, solong as the remaining portion of the leading edge progresses through aplurality of different temperature points over time as noted above.

The peak of the waveform represents the amplitude of the waveform ascompared to the subject's body temperature. In general, an amplitude ofat least 5 or 7 degrees Centigrade is preferred for both heating andcooling waveform stimulation. In general, an amplitude of up to 20degrees Centigrade is preferred for cooling waveform stimulation. Ingeneral, an amplitude of up to 8 or 10 degrees Centigrade is preferredfor heating waveform stimulus. The peak of the waveform may be truncated(that is, the waveform may reach an extended temperature plateau), solong as the desired characteristics of the leading edge, and preferablytrailing edge, are retained. For heating waveforms, truncated peaks oflong duration (that is, maximum heat for a long duration) are lesspreferred, particularly at higher heats, due to potential burningsensation.

The waveform trailing edge is preferably ramped or time-varying: thatis, the amplitude of the waveform decreases through a plurality ofdifferent temperature points over time (e.g., at least 5, 10, or 15 ormore distinct temperature points, or in some embodiments at least 50,100, or 150 or more distinct temperature points, from peak to trough).The shape of the trailing edge may be a linear ramp, a curved ramp(e.g., convex or concave; logarithmic or exponential), or a combinationthereof. A vertical cut may again be included in the waveform trailingedge, so long as the remaining portion of the trailing edge progressesthrough a plurality of different temperature points over time as notedabove.

The duration of the waveform stimulus (or the frequency of that waveformstimulus) is the time from the onset of the leading edge to either theconclusion of the trailing edge or (in the case of a vertically cutwaveform followed by a subsequent waveform). In general, each waveformstimulus has a duration, or frequency, of from one or two minutes up toten or twenty minutes.

A treatment session may have a total duration of five or ten minutes, upto 20 or 40 minutes or more, depending on factors such as the specificwaveform or waveforms delivered, the patient, the condition beingtreated, etc.

In a treatment session, a plurality of waveforms may be delivered insequence. In general, a treatment session will comprise 1, 2 or 3waveforms, up to about 10 or 20 waveforms delivered sequentially. Eachindividual waveform may be the same, or different, from the other. Whena waveform is followed by a subsequent waveform, the minimum stimuluspoint (minimum heating or cooling) between is referred to as the trough.Like a peak, the trough may be truncated, so long as the desiredcharacteristics of the trailing edge, and the following next leadingedge, are retained. While the trough may represent a return to thesubject's current body temperature, in some embodiments minor thermalstimulation (cooling or heating; e.g., by 1 or 2 degrees up to 4 or 5degrees Centigrade) may continue to be applied at the trough (or througha truncated trough).

Treatment sessions are preferably once a day, though in some embodimentsmore frequent treatment sessions (e.g. two or three times a day) may beemployed. Day-to-day treatments may be by any suitable schedule: everyday; every other day; twice a week; as needed by the subject, etc. Theoverall pattern of treatment is thus typically chronic (in contrast to“acute,” as used in one-time experimental studies).

Subjects may be treated with the present invention for any reason. Insome embodiments, disorders for which treatment may be carried outinclude, include, but are not limited to, migraine headaches (acute andchronic), depression, anxiety (e.g. as experienced in post-traumaticstress disorder (“PTSD”) or other anxiety disorders), spatial neglect,Parkinson's disease, seizures (e.g., epileptic seizures), diabetes(e.g., type II diabetes), etc.

Additional disorders and conditions that can be treated by the methodsand systems of the present invention include, but are not limited to,neuropathic pain (e.g., migraine headaches), tinnitus, brain injury(acute brain injury, excitotoxic brain injury, traumatic brain injury,etc.), spinal cord injury, body image or integrity disorders (e.g.,spatial neglect), visual intrusive imagery, neuropsychiatric disorders(e.g. depression), bipolar disorder, neurodegenerative disorders (e.g.Parkinson's disease), asthma, dementia, insomnia, stroke, cellularischemia, metabolic disorders, (e.g., diabetes), post-traumatic stressdisorder (“PTSD”), addictive disorders, sensory disorders, motordisorders, and cognitive disorders.

Sensory disorders that may be treated by the methods and apparatuses ofthe present invention include, but are not limited to, vertigo,dizziness, seasickness, travel sickness cybersickness, sensoryprocessing disorder, hyperacusis, fibromyalgia, neuropathic pain(including, but not limited to, complex regional pain syndrome, phantomlimb pain, thalamic pain syndrome, craniofacial pain, cranialneuropathy, autonomic neuropathy, and peripheral neuropathy (including,but not limited to, entrapment-, heredity-, acute inflammatory-,diabetes-, alcoholism-, industrial toxin-, Leprosy-, Epstein BarrVirus-, liver disease-, ischemia-, and drug-induced neuropathy)),numbness, hemianesthesia, and nerve/root plexus disorders (including,but not limited to, traumatic radiculopathies, neoplasticradiculopathies, vaculitis, and radiation plexopathy).

Motor disorders that may be treated by the method and apparatuses of thepresent invention include, but are not limited to, upper motor neurondisorders such as spastic paraplegia, lower motor neuron disorders suchas spinal muscular atrophy and bulbar palsy, combined upper and lowermotor neuron syndromes such as familial amyotrophic lateral sclerosisand primary lateral sclerosis, and movement disorders (including, butnot limited to, Parkinson's disease, tremor, dystonia, TouretteSyndrome, myoclonus, chorea, nystagmus, spasticity, agraphia,dysgraphia, alien limb syndrome, and drug-induced movement disorders).

Cognitive disorders that may be treated by the method and apparatuses ofthe present invention include, but are not limited to, schizophrenia,addiction, anxiety disorders, depression, bipolar disorder, dementia,insomnia, narcolepsy, autism, Alzheimer's disease, anomia, aphasia,dysphasia, parosmia, spatial neglect, attention deficit hyperactivitydisorder, obsessive compulsive disorder, eating disorders, body imagedisorders, body integrity disorders, post-traumatic stress disorder,intrusive imagery disorders, and mutism.

Metabolic disorders that may be treated by the present invention includediabetes (particularly type II diabetes), hypertension, obesity, etc.

Addiction, addictive disorders, or addictive behavior that may betreated by the present invention includes, but is not limited to,alcohol addiction, tobacco or nicotine addiction (e.g., using thepresent invention as a smoking cessation aid), drug addictions (e.g.,opiates, oxycontin, amphetamines, etc.), food addictions (compulsiveeating disorders), etc.

In some embodiments, the subject has two or more of the aboveconditions, and both conditions are treated concurrently with themethods and systems of the invention. For example, a subject with bothdepression and anxiety (e.g., PTSD) can be treated for both,concurrently, with the methods and systems of the present invention.

The methods and systems according to embodiments of the presentinvention utilize thermoelectric devices (TEDs) to induce physiologicaland/or psychological responses in a subject for medically diagnosticand/or therapeutic purposes. Subjects to be treated and/or stimulatedwith the methods, devices and systems of the present invention includeboth human subjects and animal subjects. In particular, embodiments ofthe present invention may be used to diagnose and/or treat mammaliansubjects such as cats, dogs, monkeys, etc. for medical research orveterinary purposes.

As noted above, embodiments according to the present invention utilizeTEDs to provide an in-ear stimulator for administering thermalstimulation in the ear canal of the subject. The ear canal serves as auseful conduit to the individual's vestibular system and to thevestibulocochlear nerve. Without wishing to be bound by any particulartheory, it is believed that thermal stimulation of the vestibular systemis translated into electrical stimulation within the central nervoussystem (“CNS”) and propagated throughout the brain, including but notlimited to the brain stem, resulting in certain physiological changesthat may be useful in treating various disease states (increased bloodflow, generation of neurotransmitters, etc). See, e.g., Zhang, et al.Chinese Medical J. 121:12:1120 (2008) (demonstrating increased ascorbicacid concentration in response to cold water CVS).

As illustrated in FIG. 1-3, an in-ear stimulation apparatus 10 includesa support or headband 12, earphones 14 and a controller and/or powerconnection or cable 16. The earphones 14 include an earpiece 100 that isconfigured to be positioned in the ear of a patient or subject. Althoughembodiments according to the invention are illustrated with respect totwo earpieces 100 such that stimulation may be provided in both ears, itshould be understood that the in-ear stimulation apparatus 10 in someembodiments may omit one of the earpieces 100 to provide in-earstimulation to one ear of a subject.

As illustrated in FIG. 2, the earphones 14 include a cushion 20connected to supports 22 and 24, the earpiece 100, a heat sink 50 andtwo additional, ventilated support members 60 and 62. One or morethermoelectric devices (TEDs) (not shown) may be thermally coupledbetween the earpiece 100 and the heat sink 50. Thus, the TEDs betweenthe earpiece 100 and the heat sink 50 create a temperature differencebetween the earpiece 100 and the heat sink 50 when a voltage is appliedto the TEDs so that the temperature of the earpiece 100 may be increaseand/or decreased. The efficiency with which the temperature of theearpiece 100 is changed may be increased by the heat sink 50, whichdissipates excess heat or cold from the side of the TEDs opposite theearpiece 100 into the surrounding environment. As discussed above, theear canal may serve as a useful conduit to the subject's vestibularsystem and/or to the vestibulocochlear nerve for thermal stimulation forproviding caloric vestibular stimulation (CVS) and/or cranial nervestimulation.

Thin film TEDs, Peltier coolers/heaters or transducers may be used astransducers in some embodiments, including, but not limited to, the thinfilm TEDs described in U.S. Pat. No. 6,300,150 and U.S. PatentPublication Nos. 2007/0028956 and 2006/0086118; however, any suitableTED may be used. Such thin film TEDs may also advantageously incorporatea temperature sensing function, so that temperature sensing can beaccomplished through the same device without the need for a separatetemperature sensor. Thin film TEDs are commercially available fromNextreme Thermal Solultions (Durham, N.C., USA) (e.g., OptoCooler™Series (UPT40 and UPF4), Eteg™ UPF40) and Micropelt, GmbH (Freiburg,Germany) (e.g., MPC-D303 and MPC-D305). Although embodiments accordingto the invention are described herein with respect to TEDs, it should beunderstood that any suitable type of thermal device may be used,including optical heating (e.g., using a laser) and ultrasound heating(e.g., a piezoelectric heating device). TEDs may be provided thatinclude a heat flux of 80-120 W/cm² or more. TEDs may be generallyrectangular in shape, with typical rectangular areas being about 2×1 mmor 5×2 mm or more and having a height profile of 1 mm or 0.65 mm or 0.5mm or less. The TEDs may be connected in parallel or in series toprovide thermal changes to a desired region of an earpiece and/or heatsink.

The headband 12 includes adjustable members 12 a-12 c in a slideableconfiguration for adjusting the size of the headband 12 for increasedcomfort and a better fit. However, it should be understood that otherconfigurations for supporting the headphones may be used, includingsupport bands that are positioned under the chin or over the ear, forexample, as may be used with audio earphones. As illustrated, thecushion 20 may be configured to increase comfort and/or the fit of theearpiece 100 in the subject's ear canal. For example, the cushion 20 maybe sized or may be adjustable so as to place the earpiece 100 in the earcanal without placing excessive pressure on the eardrum. The cable 16 isconnected to a printed circuit board (PCB) 18 at one end and to acontroller (not shown) on the opposite end. The PCB 18 may beelectrically connected to the TEDs between the earpiece 100 and the heatsink 50 and may provide a power supply and control signals for operatingthe TEDs, such as control signals to control desired temperatures andtemperature changes, from the controller. The earpiece 100 may furtherinclude a temperature sensor/controller so that the TEDs may provide atemperature stability, e.g., of about 0.1-0.5° C.

In this configuration, the earpiece 100 may be fit into the subject'sear as shown, e.g., in FIG. 4 (the anatomical portion of the figures isadapted from FIG. 2 of U.S. Pat. No. 4,244,377). The earpiece 100 is sodimensioned as to be insertable into the ear canal of the subject. Asillustrated, the earpiece 100 may intimately contact the ear canal so asto thermally stimulate the temporal bone in the distal portion of theexternal auditory meatus.

As illustrated in FIG. 5A-5D, the earpiece 100 may have an generallyconical shape including a rounded tip portion 102, a generally circularbase portion 104, a back facing side 106 (which faces the back side ofthe subject after insertion in the ear canal) and a front facing side108 (which faces the front or face of the subject after insertion in theear canal). As shown, for example, in FIG. 5D, the tip portion 102 maybe blunted to form a dome-shaped point. The base portion 104 defines alongitudinal centerline in the center of the base portion 104, and thecross section of the earpiece 100 decreases as a function of distanceaway from the base portion 104. As illustrated, the cross section of theearpiece 100 tapers unevenly from the base portion 104 to the tipportion 102. Thus, the tip portion 102 (which extends from the baseportion 104) is off-set from the centerline of the base portion 104,e.g., by about 10° to about 40° from a vertical axis, to provide animproved fit in the ear canal of the subject. In some embodiments, thetip portion 102 is off-set from the center of the earpiece 100 in adirection toward the front facing side 108.

The earpiece 100 may be formed of any suitable material for conductingthermal energy. In particular, the earpiece 100 may be formed of ametal, such as aluminum or an aluminum alloy, e.g., aluminum 7075, whichuses zinc as the primary alloying element. As used herein, “aluminum,”includes alloys thereof (e.g., alloys in which aluminum is thepredominant metal (typically at least 60, 80 or 90 percent by weight, ormore) along with one or more alloying elements such as copper,magnesium, manganese, silicon, and zinc). In some embodiments, theweight of the earpiece is less than about 15 grams, 12 grams, 6 grams, 4grams or less.

In some embodiments, the shape of the earpiece 100 may be customized orsemi-customized for an individual wearer. For example, differentpossible shapes are illustrated in FIGS. 6A-6D, FIGS. 7A-7D and FIGS.8A-8D, depending on the shape of the subject's ear canal.

As shown in FIGS. 9-10, the earpiece 100 may be connected to a heat sink50 by TEDs 30. As illustrated, the heat sink 50 is configured to beattached to the base portion 104 of the earpiece 100; however, the heatsink 50 is thermally isolated from the earpiece 100. The TEDs 30 areconfigured so that thermal coupling between the TEDs 30 and the baseportion 104 of the earpiece 100 may be achieved. The TEDs 30 are alsothermally coupled to the heat sink 50 on a side of the TEDs that areopposite to the earpiece 100 so as to create a thermal differentialbetween the heat sink 50 and the earpiece 100. For example, a thermallyconductive adhesive, such as a silver adhesive, may be used to mount theTEDs 30 on the heat sink 50 and the earpiece 100.

The earpiece 100 as shown in FIG. 10 includes a sleeve or sheath 130.The sheath 130 may cover and/or may be connected to (e.g., removablyconnected to, permanently connected to or formed on) the earpiece 100.In some embodiments, the sheath 130 has an inner surface portionconfigured to conformably engage the earpiece 100, and an outer surfaceto conformably engage the ear canal of the subject. Hence, heat can beconducted between (that is, to or from) each of the at least onethermoelectric transducers 30 and the ear canal through the sleeve 130to deliver CVS and/or cranial nerve stimulation to the subject.

In some embodiments, the optional sleeve 130 may comprise areas of highthermal conductivity (high-k) and areas of low thermal conductivity(low-k) such that different portions of the ear canal receive differentlevels of thermal stimulus (i.e., portions of the ear canal that areadjacent to a low-k area of the sleeve receive a weaker thermal stimulusthan portions of the ear canal that are adjacent to a high-k area of thesleeve). In some embodiments, the optional sleeve may comprise onlyhigh-k areas or only low-k areas.

In embodiments lacking the optional sleeve 130, the earpiece maysimilarly comprise high-k and low-k areas whereby portions of the earcanal may be stimulated differentially.

The optional sleeve 130 can comprise, consist of, or consist essentiallyof any suitable elastic and/or compressible material, such as a polymer,a textile (woven or non-woven) or a composite thereof. In someembodiments the polymer comprises a hydrogel polymer, a thermallyconductive resin, and/or a viscoelastic polymer (it being understoodthat some but not all viscoelastic polymers will be hydrogel polymers;and some but not all hydrogel polymers will be viscoelastic polymers).Numerous suitable hydrogel polymers, including biodegradable orbioerodable hydrogel polymers, and stable hydrogel polymers (e.g.,silicone hydrogel polymers) are known. Examples include but are notlimited to those described in U.S. Pat. Nos. 7,213,918; 7,171,276;7,105,588; 7,070,809; 7,060,051; and 6,960,625. Suitable viscoelasticpolymers include but are not limited to those described in, for example,U.S. Pat. Nos. 7,217,203; 7,208,531; and 7,191,483. An ester-basedviscoelastic memory foam such as used in the heating pad systemsdescribed in U.S. Pat. No. 7,176,419 is among those suitable for use inmaking sleeves of the present invention. In some embodiments, theoptional sleeve 130 has a thermal conductivity of from 0.1 to 50 W/m×K;and a hardness of from 0 to 50 on the Shore A scale.

The optional sleeve 130 can be made by any suitable technique such asmolding, casting, etc. While in some preferred embodiments the optionalsleeve 130 is removable, in other embodiments that sleeve is formed on,integrally formed with, or otherwise permanently connected to theearpiece 100. The optional sleeve 130 can be open at both the tipportion 102 (closest to the ear drum) and/or the base portion 104. Theoptional sleeve 130 may be transparent or tinted with a pigment, inwhole or in part such as in one or more defined locations on the sleeve(e.g., the medial portion, the outer portion, the upper portion, thelower portion, the front portion, the back portion) to provide anindicator of whether the sleeve is for a left or right ear canal device,an indicator of size of the sleeve, an indicator of how the sleeveshould be oriented on the heat sink, etc.

As shown in FIGS. 11A-11B, the heat sink 50 includes an upper portion 52that is configured to be mounted on the earpiece 100 via the TEDs tothermally couple the earpiece 100 and the heat sink 50. A lower portion54 of the heat sink 50 includes fins 56 that are spaced apart andconfigured to dissipate heat and/or cold to the surrounding environment.

In some embodiments, the heat sink 50 is formed of a thermallyconductive material, such as a metal (such as aluminum, including alloysthereof (e.g., alloys in which aluminum is the predominant metal(typically at least 60, 80 or 90 percent by weight, or more) along withone or more alloying elements such as copper, magnesium, manganese,silicon, and zinc)). As used herein, “aluminum” includes aluminumalloys, e.g., alloys having more than 50% aluminum. In particularembodiments, aluminum 6061 may be used. The heat sink 50 may weighbetween about 30 or 40 grams to between about 60 or 70. In particularembodiments, the heat sink 50 weighs 50-55 grams. The heat sink lowerportion 54 may have a diameter of about 2.4 inches (+/−20%). Thedistance from the top of the lower portion 54 to the distal end of thefins 56 may range from about 0.38 (+/−20%) for the shorter fins 56 onthe outer edge of the heat sink 54 to about 0.75 (+/−20%) for the longerfins 56 in the middle of the heat sink 50. As shown, for example, inFIG. 2, the heat sink 50 may be held in position on the headphone 14 byventilated support members 60 and 62, which include open air vents tofurther thermal dissipation from the heat sink 50.

In some embodiments, the earpiece 100, TEDs 30 and heat sink 50 may beconfigured to change the temperature of the earpiece 100 relativelyrapidly so that various thermal waveforms may be delivered to theearpiece 100, e.g., due to the thermal conductivity of the materials ofthe earpiece 100 and heat sink 50, such as the aluminum or aluminumalloys discussed herein. In some embodiments, the slew rate of theearpiece 100 may be about 10° C./minute or about 20° C./minute or less.The temperature of the earpiece 100 in some embodiments may be betweenabout 17° C. to about 46° C., or between about 17° C.-20° C. for coolingthe ear canal to about 44° C.-46° C. for warming the ear canal.

Although embodiments according to the present invention are describedherein with respect to the earpiece 100, heat sink 50 and TEDs 30, itshould be understood that in some embodiments, the earpiece 100 may beomitted and/or the heat sink 50 and earpiece 100 may be combined suchthat the TEDs 30 are placed in direct contact with the ear canal or arethermally coupled to the ear canal via an optional sleeve. Asillustrated in the schematic representation of FIG. 12 (not to scale),the heatsink 50 includes an upper portion 52 that is configured to beinserted into the ear canal and having TEDs 30 mounted thereon. Anoptional sleeve 130 may be provided, e.g., to increase comfort andwearability. The lower portion 54 of the earpiece 50 may be held inposition by a headphone, such as is described herein with respect to theheadphone 14 of FIGS. 1-2. In some embodiments, the upper portion 52 ofthe heat sink 50 is sized and shaped as described herein with respect tothe earpiece 100, and the lower portion 54 is sized and shaped asgenerally described with respect to FIGS. 11A-11B.

Exemplary controllers for controlling the thermal inputs to the TEDdevices described herein will now be discussed.

FIG. 13 is a block diagram of exemplary embodiments of controllers ofthe present invention for controlling a TED apparatus 10 to administervarious thermal treatment protocols or thermal “prescriptions.” As shownin FIG. 13, in some embodiments, the controller 212 comprises memory 220a, a processor 220 b and an internal power supply 220 c and isoperatively and communicatively coupled to a TED apparatus 200 (such asthe TED apparatus 10 described herein). The processor 220 b communicateswith the memory 220 a via an address/data bus 250. As will beappreciated by one of skill in the art, the processor 220 b may be anycommercially available or custom microprocessor. Memory 220 a isrepresentative of the overall hierarchy of memory devices containingsoftware and data used to implement the functionality of the controller212. Memory 220 a can include, but it not limited to, the followingtypes of devices: cache, ROM, PROM, EPROM, EEPROM, flash memory, SRAMand DRAM.

As shown in FIG. 13, the controller memory 220 a may comprise severalcategories of software and data: an operating system 221, applications222, data 223 and input/output (I/O) device drivers 226.

As will be appreciated by one of skill in the art, the controller mayuse any suitable operating system 221, including, but not limited to,OS/2, AIX, OS/390 or System390 from International Business MachinesCorp. (Armonk, N.Y.), Window CE, Windows NT, Windows2003, Windows2007 orWindows Vista from Microsoft Corp. (Redmond, Wash.), Mac OS from Apple,Inc. (Cupertino, Calif.), Unix, Linux or Android.

Applications 222 may comprise one or more programs configured toimplement one or more of the various features of the present invention.Applications 222 may comprise a TED thermal control module 224configured to activate the TED apparatus 200. In some embodiments, thememory 220 a comprises additional applications, such as a networkingmodule for connecting to a network. In some embodiments, the controlmodule 224 may be configured to activate at least one TED (i.e., tocontrol the magnitude, duration, waveform and other attributes ofstimulation delivered by the at least one TED). In some suchembodiments, the control module 224 is configured to activate at leastone TED based upon a prescription from the prescription database 225.The thermal prescriptions in the prescription database 225 may includeone or more sets of instructions for delivering one or more time-varyingthermal waveforms to the vestibular system of a subject. In some suchembodiments, the control module 224 is configured to selectively andseparately activate a plurality of TEDs (e.g., by activating only one ofthe plurality of TEDs, by heating one TED and cooling another, bysequentially activating the TEDs, by activating different TEDs usingdifferent temperature/timing parameters, combinations of some or all ofthe foregoing, etc.).

Data 223 may comprise static and/or dynamic data used by the operatingsystem 221, applications 222, I/O device drivers 226 and other softwarecomponents. Data 223 may comprise a thermal prescription database 225comprising one or more thermal treatment protocols. In some embodiments,the memory 220 a comprises additional data, such as data associated withthe delivery of one or more time-varying thermal waveforms, includingpatient outcomes, temperature measurements of the ear as a result of thethermal stimulation, and the like.

I/O device drivers 226 typically comprise software routines accessedthrough the operating system 221 by the applications 222 to communicatewith devices such as I/O ports, memory 220 a components and/or the TEDapparatus 200.

In some embodiments, the TED thermal control module 224 is configured toactivate at least one TED in the TED apparatus 200 to stimulate thenervous system and/or the vestibular system of a subject. In particularembodiments, the TED thermal control module 224 is configured toactivate at least one TED based upon a thermal prescription comprising aset of instructions for delivering one or more time-varying thermalwaveforms to the vestibular system of a subject.

In some embodiments, the controller 212 is operatively connected to atleast one TED in the TED apparatus 200 via a thermal stimulationconductive line. In some embodiments, the controller 212 is operativelyconnected to a plurality of TEDs, the controller 212 may be operativelyconnected to each TED via a separate thermal stimulation conductiveline. In some such embodiments, each of the plurality of separatethermal stimulation conductive lines is bundled together into one ormore leads (e.g., the thermal stimulation conductive lines connected tothe TED(s) thermally coupled to the right earpiece may be bundledseparately from the thermal stimulation conductive lines connected tothe TED(s) thermally coupled to the left earpiece). In some suchembodiments, the thermal stimulation conductive lines are connected tothe controller 212 via a lead interface (e.g., one or more leads may beconnected to the controller 212 using an 18-pin connector).

In some embodiments, the controller 212 is operatively connected to atleast one TED in the TED apparatus 200 via an electrical stimulationconductive line. In some embodiments, the controller 212 is operativelyconnected to a plurality of TEDs, and the controller may be operativelyconnected to each TED via a separate electrical stimulation conductiveline. In some such embodiments, each of the plurality of separateelectrical stimulation conductive lines is bundled together into one ormore leads (e.g., two leads, with the conductive lines connected to theTEDs in the right ear being bundled separately from the conductive linesconnected to the TEDs in the left ear). In some such embodiments, theelectrical stimulation conductive lines are connected to the controllervia a lead interface (e.g., two leads may be plugged into the controllerusing a shared 18-pin connector).

In some embodiments, the controller is operatively connected to at leastone TED in the TED apparatus 200 via a wireless connection, such as aBluetooth connection.

Exemplary thermal waveforms that may be delivered via the TED apparatus200 as controlled by the controller 212 will now be discussed.

EXAMPLE 1 Square Wave Administration

A male subject in his forties and good health was administered coldcaloric vestibular stimulation to his right ear in a square waveformpattern. The pattern was of cooling to 20 degrees Centigrade (ascompared to normal body temperature of about 37 degrees Centigrade) as a“step” function or “square wave” with one symmetric square wave beingdelivered every two five minutes minutes for a time period of 20minutes. The subject was observed by others to be slurring his words,and was asked to remain seated for a time of two hours following thetreatment session as a precaution. The subject reported a sensation ofintoxication, and subsequently reported a sense of “immunity” to thesessions in which square waves cooling was administered for the same andduration.

EXAMPLE 2 Sawtooth Wave Administration

The same subject that developed a sensation of immunity to the squarewaveform treatment described in EXAMPLE 1 was subsequently treated byadministering cold caloric vestibular stimulation to the right ear in asawtooth waveform pattern of cooling to 20 degrees Centigrade (ascompared to normal body temperature of about 37 degrees Centigrade) in asymmetric sawtooth waveform pattern, without gaps, at a frequency of onecycle or waveform every five minutes, for a total duration ofapproximately 10 minutes and a delivery of a first and second waveform.Unlike the situation with the square wave pattern described in Example1, the subject continued to perceive the temperature cycling up anddown.

EXAMPLE 3 Maximum Waveform Amplitude

The same subject described in Examples 1-2 was administered cold caloricvestibular stimulation to the right ear as a sawtooth cooling waveformat different amplitudes in a titration study. A maximum perceivedsensation of cyclic cooling was perceived at a peak amplitudes of about17 degrees Centigrade (or cooling from normal body temperature to atemperature of about 20 degrees Centigrade). Cooling beyond this did notlead to additional gains in the sensation of cyclic cooling perceived bythe subject.

EXAMPLE 4 Minimum Waveform Amplitude

Modeling of the human vestibular system indicates that the cupula (thestructure within the semicircular canals pushed by the movement of fluidtherein and which contain hair cells that convert the mechanicaldistortion to electrical signals in the vestibular nerve), is stimulatedby caloric vestibular stimulation at chilling temperatures of 5 or 7degrees Centigrade below body temperature.

EXAMPLE 5 Maximum Waveform Frequency

Modeling of the human vestibular system indicates that a slew ratefaster than 20 degrees Centigrade per minute (which would enable one 20degree Centigrade waveform every two minutes) is not useful because thehuman body cannot adapt to temperature changes at a more rapid rate.While maximum frequency is dependent in part on other factors such aswaveform amplitude, a maximum frequency of about one cycle every one totwo minutes is indicated.

EXAMPLE 6 Minimum Waveform Frequency

Modeling of the human vestibular system indicates that the a continuous,time-varying waveform is most effective in stimulating the vestibularsystem, as stagnation and adaptation of the cupula is thereby minimized.While minimum frequency is dependent in part on other factors such asthe waveform amplitude, a minimum frequency of about one cycle every tento twenty minutes is indicated.

EXAMPLE 7 Treatment Session Duration

To permit delivery of at least a first and second waveform, a durationof at least one or two minutes is preferred. As noted above and below,results have been reported by patients with treatment durations of tenand twenty minutes. Hence, as a matter of convenience, a treatmentsession duration of not more than 30 or 40 minutes is preferred.

EXAMPLE 8 Treatment of Migraine Headache with Sawtooth Waveforms

A female patient in her early fifties with a long standing history ofmigraine suffered an acute migraine episode with symptoms that consistedof a pounding headache, nausea, phonophobia, and photophobia. Right earcold caloric vestibular stimulation was performed using the sawtoothwaveform, essentially as described in Example 2 above, with atemperature maximum of 17 degrees (chilling from body temperature) for10 minutes (for a total delivery of two cycles). At the conclusion ofthe treatment the patient reported that her headache and associatedsymptoms were no longer present. At a reassessment one day later, thepatient reported that the headache had not returned.

EXAMPLE 9 Treatment of Diabetes with Sawtooth Waveforms

The same subject described in examples 1-3 suddenly developed an episodeof extreme urination (10 liters per day), thirst for ice water, andassociated fatigue. Urinary testing suggested the onset of diabetesmellitus, for which there was strong family history.

The patient's initial weight as taken at his primary care physicianindicated a recent 20 pound weight loss. The first attempt to obtain aglucose reading from the patient resulted in an out of range result(this typically occurs with glucose levels in excess of 600 mg/dl). Thepatient was hospitalized and received hydration and IV insulin therapy.The patient's first glucose level after this treatment was 700 mg/dl.The glucose level were brought down to approximately 350 and treatmentwith an oral antihyperglycemic agent was initiated.

Follow-up care after hospital discharge with the subject's primary carephysician. expanded the oral antihyperglycemic agent therapy to includeboth metformin and JANUVIA™ sitagliptin. In addition, a strict exerciseprogram of 30-45 minutes 5 to 6 days per week and diet control wereinstituted. Daily glucose levels via finger stick were taken 2 to 3times per day.

At this point the patient's baseline hemoglobin A1c (Hb A1c) level was9.8%, as compared to normal levels of 5 to 6%.

The patient then began daily treatment with caloric vestibularstimulation. The treatment was carried out for a time of ten minutes,once a day for about a month, after which the treatment was continuedtwo to three times a week for three additional months (with eachtreatment session being about 10 minutes in duration). The caloricvestibular stimulation was delivered to the patient's right ear, as asawtooth cooling waveform as described in EXAMPLE 2. At the conclusionof these treatments, the patient's HB A1c level was 5.3%. As a result,the patient was removed from all hypoglemic agents.

Most oral antihyperglycemic agents lower a patient's Hb A1c level byapproximately 1 to 2% (see generally S. Inzucchi, Oral AntihyperglycemicTherapy for Type 2 Diabetes, JAMA 287, 360-372 (Jan. 16, 2002)). Incontrast, this patient's initial value was 9.5, and dropped to 5.3.

EXAMPLE 10 Alternate Waveform Shapes

The sawtooth waveform described in the examples above was symmetric andlinear, as illustrated in FIG. 4A, where line dashed line “n” representsthe subject's normal body temperature (typically about 37 degreesCentigrade). Modeling of the vestibular system indicates that waveformsof similar amplitude and frequency, but with a variation in shape, arealso effective, such as the “logarithmic” or “convex” waveform of FIG.4B, and the “exponential” or “concave” waveform of FIG. 4C. Allwaveforms generally include a leading edge (“le”), a trailing edge(“te”), a peak (“p”) and a trough (“t”).

While FIGS. 4A through 4C all show three consecutive waveforms of thesame shape, amplitude, and frequency, the consecutive waveforms can bevaried in shape as shown in FIG. 4D, and can be varied in amplitude orduration as well (preferably each consecutive waveform within theparameters noted above), to produce still additional waveforms andsequences of waveforms which are useful in carrying out the presentinvention.

In addition, while the waveforms of FIGS. 4A through 4D are shown ascontinuous, minor disruptions can be included therein, such astruncations (“trn”; for example, as shown in FIG. 4E,) or vertical cuts(“ct”; for example, as shown in FIG. 4F) to produce still additionalwaveforms and sequences of waveforms which are useful in carrying outthe present invention.

The peak for all waveforms of FIGS. 4A-4E is cooling by 17 degreesCentigrade from normal body temperature to a temperature of 20 degreesCentigrade, and the trough for all waveforms is a return to normal bodytemperature, giving an amplitude of 17 degrees Centigrade. The frequencyfor all illustrated waveforms is 1 cycle (or one complete waveform)every five minutes. While 3 cycles of the same waveform are illustratedfor clarity, note that in some of the examples above only two cycles aredelivered over a total treatment or session duration of ten minutes.

EXAMPLE 11 Patient Orientation

It was noted that a patient who was sitting up (watching TV) andreceiving a cold caloric vestibular stimulation (CVS) treatment reportedperceiving a different effect than perceived in prior sessions. Uponreclining to about 45 degrees, she did.

The “standard” angle of recline for diagnostic CVS is about 60 degrees(or equivalently 30 degrees above horizontal). The reason for thispositioning is that the “horizontal” SCC is actually tilted up by about30 degrees (higher on rostal side). The intent with diagnostic CVS is toreorient the horizontal SCC so that it is substantially vertical, thusmaximizing the effect of the convective flow set up by calories.

Hence, if the subject is reclined to about 30 degrees above horizontal(and supine), then a cold stimulus leads to inhibition or a phasic rateless than the tonic rate. For a warm stimulus, this is reversed (phasicrate increases above tonic).

Further, cold simulation tends to activate principally the contralateralbrain structures whereas hot leads to principally ipsilateralactivation. For example, in the fMRI paper by V. Marcelli et al. (Eur.J. Radiol. 70(2): 312-6 (2009) (epub Mar. 14, 2008), the authors did aleft ear, cold stimulation by water irrigation and saw right-sideactivation in the brainstem, cerebellum, etc. The patient was presumablynearly reclined in the MRI magnet.

Empirical tests and modeling indicate that approximately 20 degreesCentigrade absolute cooling (17 degrees Centigrade below body temp) isthe lower limit beyond which the cupula is maximally deformed andtherefore the phasic rate change is maximal. On the warming side, morethan about 7 degrees above body temp becomes uncomfortable. This willnot lead to maximal deformation of the cupula. Therefore, there is anasymmetry in terms of ability to span the full frequency spectrum ofphasic firing rates. Specifically, one can't access the highestfrequencies through use of warm stimulation due to the inability to useoverly warm stimulus on a patient.

However, this is not an immutable issue. Since inverting the patientchanges the sign of the inhibitory/excitatory motion of the cupula, thefollowing can be seen: Using a cold stimulus, of 20 degrees absolute,but now orient the patient so that his head is tilted forward by 75-120degrees from vertical. This will invert the horizontal SCC relative tothe image above and now the cold stimulus will result in an excitatoryincrease in the phasic firing rate. For clarity, tilting the headforward by 30 degrees makes the horizontal SCC substantially horizontal.Tilting beyond that now starts to invert it so that at 120 degrees(tilted forward), the horizontal SCC will be in a vertical orientation,but now 180 degrees flipped from what is used in conventional diagnosticcaloric vestibular stimulation. So, the “general rule” for treatment ofhaving the patient reclined by 45-90 degrees can be expanded to include“tilted forward” by 75-120 degrees.

Thus a protocol is seen where, using only cold stimulus, one can coverthe entire range of phasic firing rates simply by reorienting thepatient at the appropriate points during the time course of treatment.

Note that this type of inversion should also lead to an inversion in theside of the brain that is primarily activated. Specifically, if coldstimulation leads principally to contralateral activation in the“rightside up” orientation, then it should lead to principallyipsilateral activation in the “upside down” orientation.

The foregoing is illustrative of the present invention and is not to beconstrued as limiting thereof. Although a few exemplary embodiments ofthis invention have been described, those skilled in the art willreadily appreciate that many modifications are possible in the exemplaryembodiments without materially departing from the novel teachings andadvantages of this invention. Accordingly, all such modifications areintended to be included within the scope of this invention as defined inthe claims. Therefore, it is to be understood that the foregoing isillustrative of the present invention and is not to be construed aslimited to the specific embodiments disclosed, and that modifications tothe disclosed embodiments, as well as other embodiments, are intended tobe included within the scope of the appended claims. The invention isdefined by the following claims, with equivalents of the claims to beincluded therein.

That which is claimed:
 1. An in-ear stimulator for administering thermalstimulation to the ear canal of a subject, comprising: (a) an earpiececonfigured to be at least partially insertable into the ear canal of thesubject; and (b) at least one thermoelectric device thermally coupled tosaid earpiece and configured to heat and/or cool said earpiece tothereby heat and/or cool the ear canal of the subject.
 2. The stimulatorof claim 1, further comprising a heat sink thermally coupled to said atleast one thermoelectric device and configured for positioned outsidethe ear canal of a subject.
 3. The stimulator of claim 2, wherein saidheat sink comprises a generally planar surface, said earpiece having acorresponding cooperating planar surface, said at least onethermoelectric device being mounted between said heat sink planarsurface and said cooperating portion of said earpiece planar surface. 4.The stimulator of claim 3, wherein the heat sink outer portion comprisesa plurality of fins.
 5. The stimulator of claim 2, wherein said heatsink comprises aluminum.
 6. The stimulator of claim 2, wherein said heatsink has a weight between about 30 grams and about 70 grams.
 7. Thestimulator of claim 1, wherein said earpiece is formed from a rigid,thermally-conductive material.
 8. The stimulator of claim 1, whereinsaid earpiece comprises aluminum.
 9. The stimulator of claim 1, whereinsaid earpiece weighs about 12 grams or less.
 10. The stimulator of claim1, wherein the at least one thermoelectric device comprises a pluralityof thermoelectric devices.
 11. The stimulator of claim 10, wherein saidplurality of thermoelectric devices are thermally coupled to oneanother.
 12. The stimulator of claim 11, wherein said at least onethermoelectric device comprises a thin film thermoelectric device. 13.The stimulator of claim 2, wherein said earpiece is thermally coupled toa first side of the at least one thermoelectric device and said heatsink is thermally coupled to an opposing second side of the at least onethermoelectric device.
 14. The stimulator of claim 1, wherein saidearpiece is conical in shape.
 15. The stimulator of claim 14, whereinsaid earpiece comprises a circular cone.
 16. The stimulator of claim 14,wherein said earpiece comprises a conical apex of the conical shape thathas been blunted to form a dome-shaped point.
 17. The stimulator ofclaim 16, wherein said earpiece comprises: a generally cylindrical basehaving opposite first and second ends, the base defining a longitudinalcenterline; and an extended portion extending from the second end of thecylindrical base, wherein said dome-shaped point is offset from thelongitudinal centerline.
 18. The stimulator of claim 17, wherein thecross-sectional area of the extended portion decreases as a function ofdistance away from said base.
 19. The stimulator of claim 18, whereinthe extended portion tapers unevenly from said cylindrical base to saiddome-shaped point.
 20. The stimulator of claim 1, further comprising ahead piece, wherein said head piece is configured for positioning theearpiece in the ear canal of the subject.
 21. An in-ear stimulator foradministering thermal stimulation to the ear canals of a subject,comprising: (a) a first earpiece configured to be at least partiallyinsertable into the right ear canal of the subject; (b) a secondearpiece configured to be at least partially insertable into the leftear canal of the subject; (c) at least one thermoelectric devicethermally coupled to said first earpiece and configured to heat and/orcool said first earpiece to thereby thermally stimulate the right earcanal of the subject; (d) at least one thermoelectric device thermallycoupled to said second earpiece and configured to heat and/or cool saidsecond earpiece to thereby thermally stimulate the left ear canal of thesubject; (e) a headpiece configured to position said first earpiece inthe right ear canal of the subject and to position said second earpiecein the left ear canal of the subject.
 22. The stimulator of claim 21,wherein said headpiece comprises a flexible or adjustable, band.
 23. Thestimulator of claim 22, further comprising: a first heat sink thermallycoupled to said at least one thermoelectric device coupled to said firstearpiece; and a second heat sink thermally coupled to said at least onethermoelectric device coupled to said first earpiece.
 24. A method fordelivering caloric stimulation to a subject, the method comprising:positioning at least a portion of an in-ear stimulator in an ear canalof the subject, said in-ear stimulator comprising: (a) an earpiececonfigured to be at least partially insertable into the ear canal of thesubject; and (b) at least one thermoelectric device thermally coupled tosaid earpiece and configured to heat and/or cool said earpiece tothereby thermally stimulate the ear canal of the subject; delivering atime-varying thermal waveform to said at least one thermoelectric devicesuch that said thermoelectric device effects corresponding temperaturechanges to said earpiece to deliver caloric stimulation to the subject.25. The method of claim 24, wherein said stimulator further comprises aheat sink positioned in said earpiece internal cavity, wherein said heatsink is thermally coupled to said at least one thermoelectric device.26. An in-ear stimulator for administering thermal stimulation to theear canal of a subject, comprising: a heat sink thermally coupled to atleast one thermoelectric device and having at least an outer portion ofsaid heat sink that is configured for positioning outside the ear canalof a subject, wherein said at least one thermoelectric device isconfigured to thermally stimulate the ear canal of the subject.
 27. Thestimulator of claim 26, wherein said heat sink further comprises aninner portion that is configured for positioning inside the ear canal ofthe subject, wherein said at least one thermoelectric device is mountedon said inner portion of said heat sink.
 28. The stimulator of claim 27,wherein the heat sink outer portion comprises a plurality of fins. 29.The stimulator of claim 26, wherein said heat sink comprises aluminum.30. The stimulator of claim 26, wherein said heat sink has a weightbetween about 30 grams and about 70 grams.
 31. The stimulator of claim27, further comprising a sleeve that extends over said heat skink innerportion and said at least one thermoelectric device.